Age-related macular degeneration and modification of systemic complement factor H production through liver transplantation

Purpose: To investigate whether modification of liver complement factor H (CFH) production, by alteration of liver CFH Y402H genotype through liver transplantation (LT), influences the development of age-related macular degeneration (AMD). Design: Multicenter, cross-sectional study. Participants: We recruited 223 Western European patients ≥55 years old who had undergone LT ≥5 years previously. Methods: We determined AMD status using a standard grading system. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype, measured using enzyme-linked immunosorbent assays. This approach was verified by genotyping donor tissue from a subgroup of patients. Systemic complement activity was ascertained by measuring levels of plasma complement proteins using an enzyme-linked immunosorbent assay, including substrates (C3, C4), activation products (C3a, C4a, and terminal complement complex), and regulators (total CFH, C1 inhibitor). Main Outcome Measures: We evaluated AMD status and recipient and donor CFH Y402H genotype. Results: In LT patients, AMD was associated with recipient CFH Y402H genotype (P = 0.036; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.4) but not with donor CFH Y402H genotype (P = 0.626), after controlling for age, sex, smoking status, and body mass index. Recipient plasma CFH Y402H protein allotype predicted donor CFH Y402H genotype with 100% accuracy (n = 49). Plasma complement protein or activation product levels were similar in LT patients with and without AMD. Compared with previously reported prevalence figures (Rotterdam Study), LT patients demonstrated a high prevalence of both AMD (64.6% vs 37.1%; OR, 3.09; P<0.001) and the CFH Y402H sequence variation (41.9% vs 36.2%; OR, 1.27; P = 0.014). Conclusions: Presence of AMD is not associated with modification of hepatic CFH production. In addition, AMD is not associated with systemic complement activity in LT patients. These findings suggest that local intraocular complement activity is of greater importance in AMD pathogenesis. The high AMD prevalence observed in LT patients may be associated with the increased frequency of the CFH Y402H sequence variation. © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

The Regulation of AMD Pathobiology by Complement Factor H

Complement factor H (CFH) is a major susceptibility gene for age-related macular degeneration (AMD); however, its impact on AMD pathobiology is unresolved. Here, the role of CFH in the development of AMD pathology in vivo was interrogated by analyzing aged Cfh+/- and Cfh-/- mice fed a high fat, cholesterol-enriched diet. Strikingly, decreased levels of CFH led to increased sub-retinal pigmented epithelium (RPE) deposit formation, specifically basal laminar deposits, following high fat diet. Mechanistically, our data show that deposits are due to CFH competition for lipoprotein binding sites in Bruch’s membrane. Interestingly and despite sub-RPE deposit formation occurring in both Cfh+/- and Cfh-/- mice, RPE damage accompanied by loss of vision occurred only in old Cfh+/- mice. We demonstrate that such pathology is a function of excess complement activation and C5a production, associated with monocyte recruitment, in Cfh+/- mice versus complement deficiency in Cfh-/- animals. Due to the CFH dependent increase in sub-RPE deposit height we interrogated the potential of CFH as a novel regulator of Bruch’s membrane lipoprotein binding and show, using human Bruch’s membrane explants, that CFH removes endogenous human lipoproteins in aged donors. Interestingly, although the CFH H402 variant shows altered binding to BrM, this does not affect its ability to remove endogenous lipoproteins. This new understanding of the complicated interactions of CFH in AMD-like pathology provides an improved foundation for the development of targeted therapies for AMD.

Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO) - conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.

In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.

Hemolytic activity of alternative complement pathway as an indicator of innate immunity in pacu (Piaractus mesopotamicus)

The objective of this study was to evaluate the methodology to establish the hemolytic activity of alternative complement pathway as an indicator of the innate immunity in Brazilian fish pacu (Piaractus mesopotamicus), in addition to verifying the influence of β-glucan as an immunostimulant. Fish were fed with diets containing 0, 0.1 and 1% β-glucan, during seven days, and then inoculated with Aeromonas hydrophila. Seven days after the challenge, they were bled for serum extraction. The methodology consisted of a kinetic assay that allows calculating the required time for serum proteins of the complement to promote 50% lysis of a rabbit red blood cell suspension. The method developed in mammals was successfully applied for pacu and determined that the hemolytic activity of the proteins of the complement system (alternative pathway) increased after the pathogen challenge, but was not influenced by the β-glucan treatment.

Oral vaccination with heat inactivated Mycobacterium bovis activates the complement system to protect against tuberculosis

Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-γ producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar.

From emotional suppression to regulated empathy : the changing face of control in the CES

Between the 1970s and the 1990s the level and type of emotionality in the Commonwealth Employment Service (the Australian national employment service) altered. Within a context of changing economic conditions and concomitant work intensification, it is argued that untenable working conditions resulted in new recruits adopting a coping strategy that led to the use rather than the suppression of emotions. The use of emotions provided workers with job satisfaction and greater control over service interactions. Management subsequently commandeered the use of emotions to complement the introduction of private sector management techniques and service delivery reforms, regaining control over worker-client interactions.

The impact of unique characteristics of projects and project-based organisations on knowledge transfer

Knowledge has been recognised as an important organisational asset that increases in value when shared; the opposite to other organisational assets which decrease in value during their exploitation. Effective knowledge transfer in organisations helps to achieve and maintain competitive advantage and ultimately organisational success. So far, the research on knowledge transfer has focused on traditional (functional) organisations. Only recently has attention been directed towards knowledge transfer in projects. Existing research on project learning has recognised the need for knowledge transfer within and across projects in project-based organisations (PBOs). Most projects can provide valuable new knowledge from unexpected actions, approaches or problems experienced during the project phases. The aim of this paper is to demonstrate the impact of unique projects characteristics on knowledge transfer in PBO. This is accomplished through review of the literature and a series of interviews with senior project practitioners. The interviews complement the findings from the literature. Knowledge transfer in projects occurs by social communication and transfer of lessons learned where project management offices (PMOs) and project managers play significant roles in enhancing knowledge transfer and communication within the PBO and across projects. They act as connectors between projects and the PBO ‘hub’. Moreover, some project management processes naturally facilitate knowledge transfer across projects. On the other hand, PBOs face communication challenges due to unique and temporary characteristics of projects. The distance between projects and the lack or weakness of formal links across projects, create communication problems that impede knowledge transfer across projects. The main contribution of this paper is to demonstrate that both social communication and explicit informational channels play important role in inter-project knowledge transfer. Interviews also revealed the important role organisational culture play in knowledge transfer in PBOs.

Management: Core concepts and applications

Building on the strengths of its popular previous edition Management: Core Concepts and Applications, 2nd Australasian edition has been thoroughly revised and updated to reflect the three keyaspects of contemporary undergraduate introductory management education: Management theory Concept application Skills development. The text's 16 chapters are presented in a lively and concise mannerideal for the typical 12 or 13 teaching weeks of a semester. Itsflexible framework allows instructors to teach students through the useof interactive tools such as case studies, exercises and projects.These action-oriented learning activities complement the text's solidfoundation of knowledge-based theory material. There is a balanced coverage of both small to medium sizedenterprises and larger multinational organisations operating inAustralia, New Zealand and the Asia-Pacific region. A critical thinkingperspective is integrated throughout the book, asking and encouragingstudents to analyse the theory in light of real-world examples. Each copy of the printed textbook comes with a free copy of the Wiley Desktop Edition:a full electronic version of the text that allows students to easilysearch for key concepts, create their own colour-coded highlights andmake electronic notes in the text for revision. Key themes of the text include: The importance of ethical and socially responsible management Recognition of the continuing need to cater for the increasing diversity of the workforce The importance of managing people, technology, knowledge and quality in achieving organisational goals An appreciation of the challenges and opportunities presented bythe ever changing environment in which contemporary managers operate.

Stepping out into the real world of education : an introduction

‘Stepping out into the real world of Education’ has been written to complement ‘Transitioning to the real world of Education’ (Millwater & Beutel, 2008). Both books are aimed at strategising the transition you are experiencing, from preservice teacher to professional educator, through issues that you will face as early career teachers from any specialist teaching strand - early childhood, primary, middle or secondary. ‘Transitioning to the real world of Education’ (Millwater & Beutel, 2008) addressed the particularities and practicalities of professional standards, life-long learning, teaching for diversity, values-education, teacher/student relationships, teaching in a digital age and teacher burnout. This text aligns with these and explores other areas, in recognition that your early career phase is the pivotal point of how much you commit to being a teacher in the long term.

Determinants of knowledge transfer and learning in hybrid public private alliances

This paper uses the case study of a hybrid public-private strategic alliance as data to complement and contrast with the traditional views on knowledge transfer and learning between alliance partners. In particular, the paper explores whether the concept of competitive collaboration conceptualized by Hamel (1991) in his seminal work holds true for all forms of strategic alliances. Conceptualizing the knowledge boundaries of organisations in alliances as a ‘collaborative membrane’, we focus attention on the permeability of these boundaries rather than the actual location of the boundaries. In this vein, we present a case study of a major public sector organization that illustrates how these principles have allowed it to start rebuilding its internal capabilities adopting a more collaborative stance and ensuring their knowledge boundaries are highly porous as they move more major projects into hybrid public private alliance contracts.

Building an ontology and process architecture for engineering asset management

Historically, asset management focused primarily on the reliability and maintainability of assets; organisations have since then accepted the notion that a much larger array of processes govern the life and use of an asset. With this, asset management’s new paradigm seeks a holistic, multi-disciplinary approach to the management of physical assets. A growing number of organisations now seek to develop integrated asset management frameworks and bodies of knowledge. This research seeks to complement existing outputs of the mentioned organisations through the development of an asset management ontology. Ontologies define a common vocabulary for both researchers and practitioners who need to share information in a chosen domain. A by-product of ontology development is the realisation of a process architecture, of which there is also no evidence in published literature. To develop the ontology and subsequent asset management process architecture, a standard knowledge-engineering methodology is followed. This involves text analysis, definition and classification of terms and visualisation through an appropriate tool (in this case, the Protégé application was used). The result of this research is the first attempt at developing an asset management ontology and process architecture.

Difference-based meta-analytic procedures for between-participant and/or within-participant designs : a tutorial review for sports and exercise scientists

The aim of this paper is to provide a contemporary summary of statistical and non-statistical meta-analytic procedures that have relevance to the type of experimental designs often used by sport scientists when examining differences/change in dependent measure(s) as a result of one or more independent manipulation(s). Using worked examples from studies on observational learning in the motor behaviour literature, we adopt a random effects model and give a detailed explanation of the statistical procedures for the three types of raw score difference-based analyses applicable to between-participant, within-participant, and mixed-participant designs. Major merits and concerns associated with these quantitative procedures are identified and agreed methods are reported for minimizing biased outcomes, such as those for dealing with multiple dependent measures from single studies, design variation across studies, different metrics (i.e. raw scores and difference scores), and variations in sample size. To complement the worked examples, we summarize the general considerations required when conducting and reporting a meta-analysis, including how to deal with publication bias, what information to present regarding the primary studies, and approaches for dealing with outliers. By bringing together these statistical and non-statistical meta-analytic procedures, we provide the tools required to clarify understanding of key concepts and principles.

Barriers to effective knowledge transfer in project-based organisations

Effective knowledge transfer can prevent the reinvention of systems and ideas as well as the repetition of errors. Doing so will save substantial time, as well as contribute to better performance of projects and project-based organisations (PBOs). Despite the importance of knowledge, PBOs face serious barriers to the effective transfer of knowledge, while their characteristics, such as unique and innovative approaches taken during every project, mean they have much to gain from knowledge transfer. As each new project starts, there is the strong potential to reinvent the process, rather than utilise learning from previous projects. In fact, rework is one of the primary factors contributing to construction industry's poor performance and productivity. Current literature has identified several barriers to knowledge transfer in organisational settings in general, and not specifically PBOs. However, PBOs significantly differ from other types of organisations. PBOs operate mainly on temporary projects, where time is a crucial factor and people are more mobile than in other organisational settings. The aim of this research is to identify the key barriers that prevent effective knowledge transfer for PBOs, exclusively. Interviews with project managers and senior managers of PBOs complement the analysis of the literature and provide professional expertise. This research is crucial to gaining a better understanding of obstacles that hinder knowledge transfer in projects. The main contribution of this research is exclusive for PBO, list of key barriers that organisation and project managers need to consider to ensure effective knowledge transfer and better project management.

Designing for engagement : building IT systems

Context The School of Information Technology at QUT has recently undertaken a major restructuring of their Bachelor of Information Technology (BIT) course. Some of the aims of this restructuring include a reduction in first year attrition and to provide an attractive degree course that meets both student and industry expectations. Emphasis has been placed on the first semester in the context of retaining students by introducing a set of four units that complement one another and provide introductory material on technology, programming and related skills, and generic skills that will aid the students throughout their undergraduate course and in their careers. This discussion relates to one of these four fist semester units, namely Building IT Systems. The aim of this unit is to create small Information Technology (IT) systems that use programming or scripting, databases as either standalone applications or web applications. In the prior history of teaching introductory computer programming at QUT, programming has been taught as a stand alone subject and integration of computer applications with other systems such as databases and networks was not undertaken until students had been given a thorough grounding in those topics as well. Feedback has indicated that students do not believe that working with a database requires programming skills. In fact, the teaching of the building blocks of computer applications have been compartmentalized and taught in isolation from each other. The teaching of introductory computer programming has been an industry requirement of IT degree courses as many jobs require at least some knowledge of the topic. Yet, computer programming is not a skill that all students have equal capabilities of learning (Bruce et al., 2004) and this is clearly shown by the volume of publications dedicated to this topic in the literature over a broad period of time (Eckerdal & Berglund, 2005; Mayer, 1981; Winslow, 1996). The teaching of this introductory material has been done pretty much the same way over the past thirty years. During this period of time that introductory computer programming courses have been taught at QUT, a number of different programming languages and programming paradigms have been used and different approaches to teaching and learning have been attempted in an effort to find the golden thread that would allow students to learn this complex topic. Unfortunately, computer programming is not a skill that can be learnt in one semester. Some basics can be learnt but it can take many years to master (Norvig, 2001). Faculty data typically has shown a bimodal distribution of results for students undertaking introductory programming courses with a high proportion of students receiving a high mark and a high proportion of students receiving a low or failing mark. This indicates that there are students who understand and excel with the introductory material while there is another group who struggle to understand the concepts and practices required to be able to translate a specification or problem statement into a computer program that achieves what is being requested. The consequence of a large group of students failing the introductory programming course has been a high level of attrition amongst first year students. This attrition level does not provide good continuity in student numbers in later years of the degree program and the current approach is not seen as sustainable.